title: Integrating precision medicine in the study and clinical treatment of a severely mentally ill person.
abstract: Background. In recent years, there has been an explosion in the number of technical and medical diagnostic platforms being developed. This has greatly improved our ability to more accurately, and more comprehensively, explore and characterize human biological systems on the individual level. Large quantities of biomedical data are now being generated and archived in many separate research and clinical activities, but there exists a paucity of studies that integrate the areas of clinical neuropsychiatry, personal genomics and brain-machine interfaces. Methods. A single person with severe mental illness was implanted with the Medtronic Reclaim(®) Deep Brain Stimulation (DBS) Therapy device for Obsessive Compulsive Disorder (OCD), targeting his nucleus accumbens/anterior limb of the internal capsule. Programming of the device and psychiatric assessments occurred in an outpatient setting for over two years. His genome was sequenced and variants were detected in the Illumina Whole Genome Sequencing Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. Results. We report here the detailed phenotypic characterization, clinical-grade whole genome sequencing (WGS), and two-year outcome of a man with severe OCD treated with DBS. Since implantation, this man has reported steady improvement, highlighted by a steady decline in his Yale-Brown Obsessive Compulsive Scale (YBOCS) score from ∼38 to a score of ∼25. A rechargeable Activa RC neurostimulator battery has been of major benefit in terms of facilitating a degree of stability and control over the stimulation. His psychiatric symptoms reliably worsen within hours of the battery becoming depleted, thus providing confirmatory evidence for the efficacy of DBS for OCD in this person. WGS revealed that he is a heterozygote for the p.Val66Met variant in BDNF, encoding a member of the nerve growth factor family, and which has been found to predispose carriers to various psychiatric illnesses. He carries the p.Glu429Ala allele in methylenetetrahydrofolate reductase (MTHFR) and the p.Asp7Asn allele in ChAT, encoding choline O-acetyltransferase, with both alleles having been shown to confer an elevated susceptibility to psychoses. We have found thousands of other variants in his genome, including pharmacogenetic and copy number variants. This information has been archived and offered to this person alongside the clinical sequencing data, so that he and others can re-analyze his genome for years to come. Conclusions. To our knowledge, this is the first study in the clinical neurosciences that integrates detailed neuropsychiatric phenotyping, deep brain stimulation for OCD and clinical-grade WGS with management of genetic results in the medical treatment of one person with severe mental illness. We offer this as an example of precision medicine in neuropsychiatry including brain-implantable devices and genomics-guided preventive health care.
authors.affiliation: Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory , NY , USA ; Stony Brook University , Stony Brook, NY , USA.
authors.forename: Jason A
authors.initials: JA
authors.lastname: O'Rawe
authors.forename: Han
authors.initials: H
authors.lastname: Fang
authors.forename: Shawn
authors.initials: S
authors.lastname: Rynearson
authors.forename: Reid
authors.initials: R
authors.lastname: Robison
authors.forename: Edward S
authors.initials: ES
authors.lastname: Kiruluta
authors.forename: Gerald
authors.initials: G
authors.lastname: Higgins
authors.forename: Karen
authors.initials: K
authors.lastname: Eilbeck
authors.forename: Martin G
authors.initials: MG
authors.lastname: Reese
authors.forename: Gholson J
authors.initials: GJ
authors.lastname: Lyon
keywords: Deep brain stimulation; Ethics; Genomics; Neurosurgery; Obsessive compulsive disorder; Whole genome sequencing